WHO現(xiàn)場主文件編寫指南

1、附件14Annex 14WHO現(xiàn)場主文件編寫指南11WHO guidelines for drafting a site master file1. 介紹 Introduction2. 目的 Purpose3. 范圍 Scope4. 現(xiàn)場主文件的內容 Content of site master file附件Appe ndix現(xiàn)場主文件的內容Content of a site master file1基于制藥檢查會議對藥品生產商編寫現(xiàn)場主文件的注釋Based on the Explanatory notes for pharmaceutical manufacturers on the pre

2、paration of a site master file of the Pharmaceutical Inspection Convention.1. 介紹 Introduction1.1 現(xiàn)場主文件是由藥品制藥商編寫的，應當包含下列具體的信息：生產廠區(qū)的質量管理方 針及活動、在指定的生產廠區(qū)實行的對藥品生產操作的生產和 /或質量控制以及在與其相 鄰的建筑物內所進行的任何緊密的完整的操作。如果只有一部分藥品生產操作在此廠區(qū) 內進行，那么在現(xiàn)場主文件中只需要描述這些操作，例如分析、包裝等。The site master file (SMF) is prepared by the pharma

3、ceutical manufacturer and should contain specific information about the quality management policies and activities of the site, the production and/or quality control of pharmaceutical manufacturing operations carried out at the named site and any closely integrated operations at adjacent and nearby

4、buildings. If only part of a pharmaceutical operation is carried out on the site, an SMF need only describe those operations, e.g. analysis, packaging, etc.1.2 當提交給監(jiān)管機構時， 現(xiàn)場主文件中應當包含對常規(guī)監(jiān)督、 有效計劃及進行 GMP 檢查有 用的、關于制造商與 GMP 相關的活動的清晰信息。When submitted to a regulatory authority, the SMF should provide clear

5、information on the manufacturer s good manufacturing practices (GMP)-related activities that can be useful in general supervision and in the efficient planning and undertaking of GMP inspections.1.3現(xiàn)場主文件中應當包含足夠的信息，但加上附件盡量不要超過2530頁。用簡單的計劃、 輪廓圖或示意圖來替代敘述性的文字是更可取的。當用A4紙張打印出時，現(xiàn)場主文件及其附件應當是可讀的。An SMF shoul

6、d contain adequate information but, as far as possible, not exceed 25 pages plus appendices. Simple plans, outline drawings or schematic layouts are preferred instead of narratives. The SMF, including appendices, should be readable when printed on A4 paper sheets.1.4 現(xiàn)場主文件應是制造商質量管理體系文件的一部分，且應持續(xù)更新?，F(xiàn)場

7、主文件應有版 本號、生效期和必須對其進行審核的日期。應當定期對現(xiàn)場主文件進行回顧以保證其包 含了最新的信息和代表了當前所進行的活動。每個附件可以有單獨的生效期，以便進行獨立的更新。The SMF should be a part of documentation belonging to the quality management system of the manufacturer and kept updated accordingly. The SMF should have an edition number, the date it becomes effective and th

8、e date by which it has to be reviewed. It should be subject to regular review to ensure that it is up to date and representative of current activities. Each annex can have an individual effective date, allowing for independent updating.2. 目的 Purpose 這些注釋的目的是：在藥品制造商編寫現(xiàn)場主文件時提供指導，現(xiàn)場主文件在監(jiān)管機構 計劃和進行 GMP 檢

9、查時有用的。The aim of these explanatory notes is to guide the manufacturer of medicinal products in the preparation of an SMF that is useful to the regulatory authority in planning and conducting GMP inspections.3. 范圍 Scope 這些注釋適用于現(xiàn)場主文件的編寫及內容的確定。制造商應參照區(qū)域性的和 /或國家監(jiān)管 要求來確定編寫現(xiàn)場主文件是否是強制性的要求。These explanatory

10、notes apply to the preparation and content of the SMF. Manufacturers should refer to regional and or national regulatory requirements to establish whether it is mandatory for manufacturers of medicinal products to prepare an SMF.這些注釋適用于各種制造操作，例如各種藥品的生產、包裝和貼簽、檢測、重新貼簽和 重新包裝。本指南中的概述也可用于指導血液和組織制品和原料藥( A

11、PI )制造商編寫現(xiàn) 場主文件或相應的文件。These explanatory notes apply for all kinds of manufacturing operations such as production, packaging and labelling, testing, relabelling and repackaging of all types of medicinal products. The outlines of this guide could also be used in the preparation of an SMF or correspond

12、ing document by blood and tissue establishments and manufacturers of active pharmaceutical ingredients (APIs).4. 現(xiàn)場主文件的內容 Content of site master file 格式參照附件。Refer to the Appendix for the format to be used.附件 Appendix場主文件的內容 Content of a site master file1. 制造商基本信息 General information on the manufactu

13、rer1.1 制造商聯(lián)系信息 Contact information on the manufacturer- 制造商名稱及官方地址；name and official address of the manufacturer;- 生產廠地名稱及街道地址，在生產廠地內的建筑物和生產單元；names and street addresses of the site, buildings and production units located on thesite;- 制造商聯(lián)系信息，包括在產品缺陷或召回時，相關聯(lián)系人的 24 小時聯(lián)系號碼；以及 contact information of th

14、e manufacturer including 24 -hour telephone number of the contact personnel in the case of product defects or recalls; and- 生產廠地的識別碼，例如全球地位系統(tǒng)( GPS )詳細信息、生產廠地或其它地理系統(tǒng) D-U-N-S (數(shù)據(jù)通用編號系統(tǒng))編號(由 Dun & Bradstreet提供的識別碼)。identification number of the site as e.g. global positioning system (GPS) details,D-U-N-

15、S (Data Universal Numbering System) number (a unique identification number provided by Dun & Bradstreet) of the site or any other geographical location system.1.2 生產廠地被授權的藥品生產活動Authorized pharmaceutical manufacturing activities of the site- 主管部門頒發(fā)的有效的生產許可證的復印件作為附件一；或者當適用時，索引到EudraGMP 數(shù)據(jù)庫。如果主管部門不頒發(fā)生產

16、許可證，應當進行聲明。copy of the valid manufacturing authorization issued by the relevant competent authority in Annex 1; or when applicable, reference to the EudraGMP database. If the competent authority does not issue manufacturing authorizations, this should be stated;- 如果沒有涵蓋在生產許可證范圍時， 簡述由相關主管部門， 包括國外監(jiān)管機構

17、授權的制造、 進口、出口、分發(fā)和其他活動，授權的劑型 /活動，應根據(jù)許可的劑型 /活動分別敘述； brief description of manufacture, import, export, distribution and other activities asauthorized by the relevant competent authorities including foreign authorities with authorized dosage forms/activities, respectively; where not covered by the manufa

18、cturing authorization;- 在超出附件一或 EudraGMP 數(shù)據(jù)庫范圍時，將目前在生產廠地生產的所有產品類型列出 (附件二)；type of products currently manufactured on -site (list in Annex 2) where not covered by Annex 1 or the EudraGMP database; and- 列出最近 5 年內接受的所有 GMP 檢查，包括進行檢查的監(jiān)管部門名稱 / 國家和檢查日期。 如果有的話，應將現(xiàn)行 GMP 證書的復印件作為附件三或索引到 EudraGMP 數(shù)據(jù)庫。list of

19、GMP inspections of the site within the last five years; including dates and name/country of the competent authority having performed the inspection. A copy of the current GMP certificate (Annex 3) or reference to the EudraGMP database should be included, if available.1.3 在生產廠地進行的其他生產活動Any other manu

20、facturing activities carried out on the site- 如果有的話，對生產廠地內的非藥品生產活動進行描述。description of non -pharmaceutical activities on site, if any.2. 質量管理 Quality management2.1 制造商的質量管理體系 The quality management system of the manufacturer- 公司質量管理體系簡介以及采取的標準；brief description of the quality management systems run b

21、y the company and reference to the standards used;- 包括高層管理人員在內的與維護質量體系相關的人員的職責；以及responsibilities related to the maintaining of the quality system including senior management; and- 生產廠地被認證和確認的活動信息，包括認證的日期和內容，認證機構的名稱； information on activities for which the site is accredited and certified, including

22、 dates 頁碼： 6 / 15and contents of accreditations, and names of accrediting bodies.2.2 成品放行程序 Release procedure of finished products- 負責批確認的質量受權人資質要求(教育背景和工作經驗)和放行程序的詳細描述；detailed description of qualification requirements (education and work experience) of the authorized person(s)/qualified person(s)

23、responsible for batch certification and releasing procedures;- 批確認和放行程序的總體描述； general description of batch certification and releasing procedure;- 質量受權人在成品待驗和放行、評價上市許可時所扮演的角色；role of authorized person/qualified person in quarantine and release of finished products and in assessment of compliance wit

24、h the marketing authorization;- 當有多個質量受權人時，不同質量受權人之間職責的分工；以及the arrangements between authorized persons/qualified persons when several authorized persons/qualified persons are involved; and- 聲明控制策略中是否包括過程分析技術( PAT )和實時放行或參數(shù)放行。statement on whether the control strategy employs process analytical techn

25、ology (PAT) and/or real -time release or parametric release.2.3 供應商和承包商的管理 Management of suppliers and contractors- 對供應鏈的建立 / 知識和外部審計程序進行小結；a brief summary of the establishment/knowledge of supply chain and the external audit programme;- 簡述承包商、 API 制造商和其它關鍵物料供應商的確認系統(tǒng)；a brief description of the quali

26、fication system of contractors, manufacturers of APIs and other critical materials suppliers;- 為保證所生產的產品符合傳染性動物海綿狀腦病( TSE )相關指南所采取的措施； measures taken to ensure that products manufactured are compliant with transmitting animal spongiform encephalopathy (TSE) guidance;- 當懷疑或確認有不合格的 /假的/錯誤貼標簽 /偽造的 /仿冒的

27、藥品、待包裝產品(例如未包裝的片劑）、API或輔料時所采取的措施；measures adopted where substandard/spurious/falsely -labelled/falsified/counterfeit medical products, bulk products （i.e. unpacked tablets）, APIs or excipients are suspected or identified;- 采用的與生產和分析相關外部的科學、分析或其它的技術支持；use of outside scientific, analytical or other te

28、chnical assistance in relation to manufacture and analysis;- 委托生產商和實驗室清單， 包括外包的生產和 QC 活動的地址和聯(lián)系信息、 供應鏈流程圖， 例如無菌工藝中使用的內包材的滅菌、 起始物料的檢驗等， 上述信息在附件四中進行描述； 以及l(fā)ist of contract manufacturers and laboratories including the addresses and contact information and flowcharts of supply chains for outsourced manufa

29、cturing and QC activities, e.g. sterilization of primary packaging material for aseptic processes, testing of starting raw materials, etc., should be presented in Annex 4; and- 合同雙方關于上市許可符合性職責的概述（如果沒有在 2.2 中進行描述的話）brief overview of the responsibility sharing between the contract giver and acceptor w

30、ith respect to compliance with the marketing authorization （where not included under 2.2）.2.4 質量風險管理 Quality risk management-簡述制造商采用的質量風險管理（QRM ）方法學；以及brief description of quality risk management （QRM） methodologies used by the manufacturer; and-質量風險管理（QRM ）的范圍和聚焦點，包括在公司層面進行的和局部進行的風險管理 活動的簡述。應對任何運用質

31、量風險管理（QRM）系統(tǒng)評價供應連續(xù)性的活動進行描述。scope and focus of QRM including brief description of any activities which are performed at corporate level, and those which are performed locally. Any application of the QRM system to assess continuity of supply should be mentioned.2.5 產品質量回顧 Product quality reviews- 簡述采用

32、的產品質量回顧的方法學。brief description of methodologies used.3. 人員 Personnel- 組織機構圖，顯示出質量管理、生產和質量控制之間的安排，在附件五中列出，包括高管 和質量受權人，應列出職位 /職務；以及organization chart showing the arrangements for quality management, production and quality control positions/titles in Annex 5, including senior management and authorized p

33、erson(s)/qualified person(s); and- 分別列出參與質量管理、生產、質量控制、儲存和分發(fā)的員工人數(shù)；number of employees engaged in the quality management, production, quality control, storage and distribution, respectively.4. 設施和設備 Premises and equipment4.1 設施 Premises- 對生產車間的簡短描述： 尺寸和建筑物清單。 如果供應到不同市場的產品在不同的建筑物 內進行生產， 例如國內或區(qū)域所屬經濟區(qū)， 則

34、應在建筑物清單中列出并標明生產的產品所 供應的市場（如果沒有在 1.1 中說明的話）short description of plant: size of the site and list of buildings. If the production for different markets, i.e. for local country or regional economic areas, takes place in different buildings on the site, the buildings should be listed with destined marke

35、ts identified （if not identified under 1.1）;- 生產區(qū)域的簡短描述或計劃，并標示出相應的規(guī)模（不要求提供建筑或工程圖紙）simple plan or description of manufacturing areas with indication of scale （architecturalor engineering drawings are not required）;- 生產區(qū)域平面圖和流程圖（在附件六中列出） ，標示出房間潔凈級別、相鄰區(qū)域之間的壓 差以及房間內的生產活動（例如配藥、灌裝、儲存、包裝等） ；layouts and flo

36、wcharts of the production areas （in Annex 6） showing the room classification and pressure differentials between adjoining areas and indicating the production activities (i.e. compounding, filling, storage, packaging, etc.) in the rooms;- 倉庫和存儲區(qū)平面圖，如果有的話，平面圖中應標示出儲存和處理高毒性、高危害性和高 敏感性的物料的特殊區(qū)域；以及l(fā)ayouts

37、of warehouses and storage areas, with special areas for the storage and handling of highly toxic, hazardous and sensitizing materials indicated, if applicable; and- 如果有的話，簡述沒有在平面圖中標出的特殊儲存條件。brief description of specific storage conditions if applicable, but not indicated on the layouts.4.1.1 采暖、通風和空

38、調( HVAC )系統(tǒng)的簡述Brief description of heating, ventilation and air-conditioning (HVAC) systems- 確定空氣供應量、溫度、濕度、壓差、換氣率和空氣再循環(huán)方針的原則。principles for defining the air supply, temperature, humidity, pressure differentials and air-change rates, policy of air recirculation (%).4.1.2 水系統(tǒng)簡述 Brief description of wa

39、ter systems- 使用的水的質量參照；以及quality references of water produced; and- 在附件七中列出水系統(tǒng)原理圖。schematic drawings of the systems in Annex 7.4.1.3 其他相關公用設施，例如蒸汽、壓縮空氣和氮氣系統(tǒng)等的簡述Brief description of other relevant utilities such as steam, compressed air, nitrogen, etc.4.2 設備 Equipment4.2.1 主要生產和控制實驗室設備清單作為附件八，并標示出關鍵設

40、備。Listing of major production and control laboratory equipment with critical pieces of equipment identified should be provided in Annex 8.4.2.2 清潔和衛(wèi)生 Cleaning and sanitation- 描述與產品接觸的表面的清潔和衛(wèi)生方法(例如手工清潔、自動在線清潔等)brief description of cleaning and sanitation methods of product contact surfaces (i.e. manu

41、al cleaning, automatic clean -in-place, etc.).4.2.3 良好生產規(guī)范關鍵計算機化系統(tǒng)Good manufacturing practices critical computerized systems- GMP 關鍵計算機化系統(tǒng)的描述(除設備的可編程邏輯控制器( PLC )外)。description of GMP critical computerized systems (excluding equipment specific programmable logic controllers (PLCs).5. 文件記錄 Documentati

42、on- 文件記錄系統(tǒng)的描述(例如電子、手工) ；以及description of documentation system (i.e. electronic, manual); and- 當文件和記錄不在生產廠地保存或存檔(如果適用的話，包括藥物警戒數(shù)據(jù))時：列出文 件/記錄的種類；儲存地的名稱和地址；從儲存地取回文件所需要的預計時間。When documents and records are stored or archived off -site (including pharmacovigilance data, when applicable): list of types of d

43、ocuments/records; name and address of storage site; and an estimate of time required to retrieve documents from the off -site archive.6. 生產 Production6.1 產品種類 Type of productsReferences to Annex 1 or 2 can be made. 可索引到附件一或附件二。- 生產產品的類型包括：type of products manufactured including:列出在生產廠地生產的人用藥和獸用藥的劑型；

44、list of dosage forms of both human and veterinary products which are manufacturedon the site ；列出在生產廠地生產的用于臨床研究的研究藥用產品(IMP)的劑型，當其生產不同于商業(yè)化生產時，還應對生產區(qū)域和人員進行描述；list of dosage forms of investigational medicinal products (IMP) manufactured for any clinical trials on the site, and when different from the co

45、mmercial manufacturing, information on production areas and personnel; 處理的有毒或有害物質(例如有高藥理活性和 /或高致敏性)；toxic or hazardous substances handled (e.g. with high pharmacological activity and/or with sensitizing properties); 如果適用的話，在專用區(qū)域內或基于階段性生產的產品類型product types manufactured in a dedicated facility or on a

46、 campaign basis, if applicable; and 如果適用的話， PAT 應用：相關技術的總體聲明；及相關的計算機化系統(tǒng)。 PAT applications, if applicable: general statement of the relevant technology; and associated computerized systems.6.2 工藝驗證 Process validation- 工藝驗證總方針簡述；以及brief description of general policy for process validation; and- 返工或重新加

47、工方針。policy for reprocessing or reworking.6.3 物料管理和倉庫 Material management and warehousing- 起始物料、包裝材料、待包裝品和成品的處理，包括取樣、待驗、放行和儲存；以及 arrangements for the handling of starting materials, packaging materials, bulk and finished products including sampling, quarantine, release and storage; and- 不合格物料和產品的處理ar

48、rangements for the handling of rejected materials and products.7. 質量控制 Quality control- 描述在生產廠地的 QC 活動，包括物理、化學、微生物和生物檢測。description of the QC activities carried out on the site in terms of physical, chemical and microbiological and biological testing.8. 分發(fā)、投訴、產品缺陷和召回Distribution, complaints, product

49、 defects and recalls8.1 分發(fā)(生產商的職責部分)Distribution (to the part under the responsibility of the manufacturer)- 接收產品的公司的類型(批發(fā)許可證持有者、生產許可證持有者等)和位置(國家或區(qū)域 經濟區(qū))；types (wholesale licence holders, manufacturing licence holders, etc.) and locations (countries or regional economic areas) of the companies to wh

50、ich the products are shipped from the site;- 用于核實每位客戶 /接收者具有合法的資質來接收從生產商運送過來的藥品的系統(tǒng)； description of the system used to verify that each customer/recipient is legally entitled to receive medicinal products from the manufacturer;- 簡述在運輸過程中用于保證適當?shù)沫h(huán)境條件的系統(tǒng)，例如溫度監(jiān)控/控制；brief description of the system to ensure appropriate enviro